The goal of this proposal is to identify the ligand(s) and to characterize RGS/G-protein coupled pathway(s) controlling RGS expression, GAP activity, and down stream responses in liver of fasted and fed mice. We found that RGS/G protein signaling regulates transitions from the fasted to fed state. G protein coupled receptors in the central nervous system and periphery convey many of the important signals that regulate feeding behavior. We will investigate how fatty acids, hormones, and/or neuroendocrine factors regulate the expression of Regulators of G protein Signaling (RGS) proteins, and their G protein substrates, in fasted and fed mice. Our work showed that RGS proteins are critical regulators of Gi- and Gq-signaling, both to assemble signaling complexes and to provide feedback regulation of signaling pathways. RGS proteins are GTPase activating proteins (GAPs) that inhibit G protein signaling. Our hypothesis is that RGS GAP activity is regulated by preprandial and satiety signals to control G protein signaling pathways in liver. We found that RGS mRNA is up-regulated by fasting and down-regulated by feeding in a leptin-dependent manner. Our hypothesis is that this RGS gene is a feedback regulator of G protein signaling pathway(s) that controls fatty acid oxidation. To test this hypothesis we propose the following Specific Aims. Aim 1: Determine if RGS transgenic expression regulates feeding, fatty acid and/or glucose metabolism. Aim 2: Determine if RGS deficiency alters feeding or disrupts fatty acid and glucose metabolism. Aim 3: Identify the preprandial agonist(s) that induce RGS expression. [unreadable] [unreadable]